title: G6PC3 mutations are associated with a major defect of glycosylation: a novel mechanism for neutrophil dysfunction.
abstract: Glucose-6-phosphatase, an enzyme localized in the endoplasmic reticulum (ER), catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and inorganic phosphate. In humans, there are three differentially expressed glucose-6-phosphatase catabolic genes (G6PC1-3). Recently, it has been shown that mutations in the G6PC3 gene result in a syndrome associating congenital neutropenia and various organ malformations. The enzymatic function of G6PC3 is dependent on G6P transport into the ER, mediated by G6P translocase (G6PT). Mutations in the gene encoding G6PT result in glycogen storage disease type-1b (GSD-1b). Interestingly, GSD-1b patients exhibit a similar neutrophil dysfunction to that observed in G6PC3-deficient patients. To better understand the causes of neutrophil dysfunction in both diseases, we have studied the neutrophil nicotinamide adenine dinucleotide phosphate (NADPH) oxidase of patients with G6PC3 and G6PT syndromes. Unexpectedly, sodium dodecyl sulfate-polyacrylamide gel electrophoresis experiments indicated hypo-glycosylation of gp91(phox), the electron-transporting component of the NADPH oxidase, in all of these patients. Rigorous mass spectrometric glycomic profiling showed that most of the complex-type antennae which characterize the neutrophil N-glycome of healthy individuals were severely truncated in the patients' neutrophils. A comparable truncation of the core 2 antenna of the O-glycans was also observed. This aberrant neutrophil glycosylation is predicted to have profound effects on the neutrophil function and merit designation of both syndromes as a new class of congenital disorders of glycosylation.
authors.affiliation: Department of Molecular Medicine, University College London, UK.
authors.forename: Bu'hussain
authors.initials: B
authors.lastname: Hayee
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Antonopoulos
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Murphy
authors.forename: Farooq Z
authors.initials: FZ
authors.lastname: Rahman
authors.forename: Gavin
authors.initials: G
authors.lastname: Sewell
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Smith
authors.forename: Sara
authors.initials: S
authors.lastname: McCartney
authors.forename: Mark
authors.initials: M
authors.lastname: Furman
authors.forename: Georgina
authors.initials: G
authors.lastname: Hall
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Bloom
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Haslam
authors.forename: Howard R
authors.initials: HR
authors.lastname: Morris
authors.forename: Kaan
authors.initials: K
authors.lastname: Boztug
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.forename: Bryan
authors.initials: B
authors.lastname: Winchester
authors.forename: Edgar
authors.initials: E
authors.lastname: Pick
authors.forename: David C
authors.initials: DC
authors.lastname: Linch
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Gale
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Smith
authors.forename: Anne
authors.initials: A
authors.lastname: Dell
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Segal
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D004721:Endoplasmic Reticulum; D005260:Female; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D005953:Glycogen Storage Disease Type I / Q000235:genetics*; D054794:Glycomics; D006031:Glycosylation; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000502:physiology*; D010375:Pedigree; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism*; D016897:Respiratory Burst; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D055815:Young Adult
chemical_list: D008562:Membrane Glycoproteins; D011134:Polysaccharides; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D005952:Glucose-6-Phosphatase; C492193:G6PC3 protein, human